Development of novel NLRP3 inflammasome inhibitors for intervening in Alzheimer's disease

开发用于干预阿尔茨海默病的新型 NLRP3 炎性体抑制剂

• 批准号: 10631193
• 负责人: Shijun Zhang
• 金额: $ 140.33万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631193
• 关键词: 3xTg-AD mouse; AD transgenic mice; Adaptor Signaling Protein; Address; Affinity; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Ames Assay; Animal Disease Models; Animal Model; Binding; Binding Proteins; Binding Sites; Biologic Characteristic; Biological Availability; Biological Products; Biophysics; CASP1 gene; Canis familiaris; Cell Death; Cellular Assay; Cellular Stress; Chemicals; Clinical; Clinical Research; Clinical Trials; Dementia; Dependence; Development; Disease; Dose; Drug Kinetics; Drug Targeting; Evaluation; Family; Formulation; Future; Generations; Goals; IL18 gene; Immunology; In Vitro; Inflammasome; Inflammatory; Inflammatory Response; Innate Immune Response; Interleukin-1 beta; Investigational Drugs; Lead; Metabolic; Methods; Mus; Natural Immunity; Neurodegenerative Disorders; Neurology; Oral; Oral Administration; Pathogenesis; Permeability; Pharmaceutical Chemistry; Phosphotransferases; Plasma Proteins; Play; Preventive; Production; Property; Proteins; Public Health; Publishing; Rattus; Regimen; Reporting; Research; Rodent; Role; Specificity; Structure-Activity Relationship; Sulfonamides; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Toxicology; Validation; analog; blood-brain barrier penetration; candidate identification; candidate selection; cell injury; chemical synthesis; clinical candidate; cognitive function; compound 30; cytokine; design; drug development; drug discovery; flexibility; human disease; improved; in silico; in vivo; inhibitor; manufacture; marenostrin; meetings; microbial products; mouse model; multidisciplinary; neuroinflammation; novel; patient response; pharmacologic; pre-clinical; protein complex; receptor; scaffold; scale up; sensor; small molecule; small molecule libraries; therapeutic candidate; therapeutically effective

Neuroinflammation has been recognized as an essential player in the pathogenesis of Alzheimer’s disease (AD). Recently, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a multimeric protein complex that tightly regulates the innate immune responses, has been suggested with critical roles in AD development and progression. Dysregulation of the NLRP3 inflammasome is responsible for the over production of pro-inflammatory interleukin (IL)-1β and IL-18, ultimately leading to inflammatory responses and cell death. Thus, NLRP3 inflammasome represents an attractive drug target for AD and offers promise to provide effective disease modifying potential. Over the past several years, our team has successfully developed novel small molecule NLRP3 inflammasome selective inhibitors (NSIs). We originally reported NSIs with sulfonamide containing chemical scaffolds, and have established a small molecule library containing > 200 compounds with various biological characteristics. Proof of concept studies of our 1st generation lead NSI in transgenic AD mouse models demonstrated target engagement and in vivo efficacy to reduce neuroinflammation and improve cognitive functions. Our recent medicinal chemistry campaign led to the identification of new lead NSIs with significantly improved potency and binding affinity. Furthermore, our accumulated structure-activity relationship (SAR) studies have identified key structural features of the scaffolds for further optimization. The central hypothesis of this proposal is that structural optimization of the current two preclinical lead NSIs will be achieved by designing new viable analogs and isolating potent and orally available NSIs with improved pharmacokinetic (PK) properties (Aim 1), and that pharmacological suppression of the NLRP3 inflammasome by our NSIs will mitigate neuroinflammation and improve cognitive functions in preclinical AD animal models (Aim 2), which will be further evaluated by preclinical Investigational New Drug (IND)-enabling studies (Aim 3) to advance to clinical studies. For our hypothesis, the goal of this application is to accomplish preclinical IND-enabling studies on at least one candidate NSI and prepare for a meeting with the FDA and subsequent IND filing. Three aims are proposed to achieve our objectives. In Aim 1, new analogs of the lead NSIs will be designed, synthesized and biologically characterized to build a dynamic drug discovery and development pipeline. In Aim 2, selected NSIs from aim 1 will be tested for PK/PD properties in various animal models including AD mouse models. In aim 3, the top candidate NSI identified from Aim 2 will be subjected to IND-enabling studies including GMP production, GLP toxicology studies in rodents and dogs, and oral formulation development to prepare for IND filing and clinical trials. The proposed research is highly significant because we are developing a novel class of NSIs that will offer great promise to provide novel and effective therapeutics for AD, a devastating neurodegenerative disorder without cure currently.

神经炎症已被认为是阿尔茨海默氏病发病机理的重要参与者 疾病（AD）。最近，含有3（NLRP3）炎性体的点头样受体家族pyrin结构域，一个 已提出了严格调节先天免疫反应的多聚体蛋白质复合物 在广告开发和发展中的关键作用。 NLRP3炎性体的失调负责 过度产生促炎性白细胞介素（IL）-1β和IL-18，最终导致炎症 反应和细胞死亡。那就是NLRP3炎性体代表着广告的吸引人的药物目标，并提供 承诺提供有效的疾病改变潜力。在过去的几年中，我们的团队有 成功地开发了新型的小分子NLRP3炎性体选择性抑制剂（NSIS）。我们最初 报道了含有化学支架的磺酰胺的NSI，并建立了一个小分子文库 包含具有各种生物学特征的200种化合物。我们第一的概念证明 转基因AD小鼠模型中的发电铅NSI表明目标参与和体内效率 减少神经炎症并改善认知功能。我们最近的药物化学运动导致 鉴定具有显着提高效力和结合亲和力的新铅NSI。此外，我们的 累积的结构活性关系（SAR）研究确定了脚手架的关键结构特征 以进一步优化。该提议的核心假设是当前两个的结构优化 通过设计新的可行类似物并隔离潜力和口服可用的临床前铅NSI NSI具有改进的药代动力学（PK）特性（AIM 1），并抑制药理学抑制 NSIS的NLRP3炎性体将减轻神经炎症并改善认知功能 临床前AD动物模型（AIM 2），将通过临床前研究新药进一步评估 （IND） - 增强研究（目标3）以促进临床研究。对于我们的假设，此应用的目的是 完成至少一个候选人NSI的临床前指定研究，并为与 FDA和随后的IND备案。提出了三个目标来实现我们的目标。在AIM 1中，新的类似物 NSI铅的铅将被设计，合成和生物学特征来建立动态药物发现 和开发管道。在AIM 2中，将对AIM 1中选定的NSIS进行各种PK/PD属性测试 包括AD鼠标模型在内的动物模型。在AIM 3中，AIM 2确定的最高候选NSI将是 经过辅助研究，包括GMP的产生，啮齿动物和狗的GLP毒理学研究以及 口服配方开发以准备IND提交和临床试验。拟议的研究高度 意义重大，因为我们正在开发一类新型的NSI，这些NSI将提供巨大的希望提供小说和 AD的有效疗法，目前无法治愈的毁灭性神经退行性疾病。